Pulmonary diseases or disorders frequently involve or trigger both inflammation and fibrosis. For example, Acute Respiratory Distress Syndrome (ARDS) is characterized by an acute pulmonary inflammatory process with epithelial apoptosis and interstitial and inter-alveolar edema, followed by fibroblast proliferation, migration and fibrosis. Similarly, acute lung injury, induced, for example, by inhalation of toxic substances, infection, or as a side effect of drug therapy (e.g., chemotherapy with bleomycin), can result in inflammation and fibrosis.
Pulmonary fibrosis of unknown etiology is known as Idiopathic Pulmonary Fibrosis (IPF). It is of insidious onset with nonproductive cough and dyspnea. The estimated five year survival is 30-50%, with a mean survival from the time of diagnosis of 2-4 years (Am. J. Resp. Crit. Care. Med. 161:646-664 (2000)).
The pathology of IPF is multifactorial. Bronchoalveolar lavage shows an increase in PMNs, eosinophils, alveolar macrophages, and lymphocytes, as well as increased levels of cytokines, growth factors, and immune complexes. The common final pathway is fibrosis of lung parenchyma with increasing respiratory insufficiency and eventual respiratory failure.
Corticosteroids and cytotoxic agents have been a mainstay of therapy, with only 10-30% of patients showing an initial transient response, suggesting the need for long-term therapy (Mapel et al., Chest 110: 1058-1067 (1996); Raghu et al., Am. Rev. Respir. Dis. 144:291-296 (1991)).
The insulin-like growth factor receptor (IGF-1R) is a ubiquitous transmembrane tyrosine kinase receptor that is essential for normal fetal and post-natal growth and development. IGF-1R can stimulate cell proliferation, cell differentiation, changes in cell size, and protect cells from apoptosis. It has also been considered to be quasi-obligatory for cell transformation (reviewed in Adams et al., Cell. Mol. Life. Sci. 57:1050-93 (2000); Baserga, Oncogene 19:5574-81 (2000)). The IGF-1R is located on the cell surface of most cell types and serves as the signaling molecule for growth factors IGF-I and IGF-II (collectively termed henceforth IGFs). IGF-1R also binds insulin, albeit at three orders of magnitude lower affinity than it binds to IGFs. IGF-1R is a pre-formed hetero-tetramer containing two alpha and two beta chains covalently linked by disulfide bonds. The receptor subunits are synthesized as part of a single polypeptide chain of 180 kd, which is then proteolytically processed into alpha (130 kd) and beta (95 kd) subunits. The entire alpha chain is extracellular and contains the site for ligand binding. The beta chain possesses the transmembrane domain, the tyrosine kinase domain, and a C-terminal extension that is necessary for cell differentiation and transformation, but is dispensable for mitogen signaling and protection from apoptosis.
IGF-1R is highly similar to the insulin receptor (IR), particularly within the beta chain sequence (70% homology). Because of this homology, recent studies have demonstrated that these receptors can form hybrids containing one IR dimer and one IGF-1R dimer (Pandini et al., Clin. Canc. Res. 5:1935-19 (1999)). The formation of hybrids occurs in both normal and transformed cells and the hybrid content is dependent upon the concentration of the two homodimer receptors (IR and IGF-1R) within the cell. Although hybrid receptors are composed of IR and IGF-1R pairs, the hybrids bind selectively to IGFs, with affinity similar to that of IGF-1R, and only weakly bind insulin (Siddle and Soos, The IGF System. Humana Press. pp. 199-225 (1999)). These hybrids therefore can bind IGFs and transduce signals in both normal and transformed cells.
A second IGF receptor, IGF-IIR, or mannose-6-phosphate (M6P) receptor, also binds IGF-II ligand with high affinity, but lacks tyrosine kinase activity (Oates et al., Breast Cancer Res. Treat. 47:269-81 (1998)). Because it results in the degradation of IGF-II, it is considered a sink for IGF-II, antagonizing the growth promoting effects of this ligand. Loss of the IGF-IIR in tumor cells can enhance growth potential through release of its antagonistic effect on the binding of IGF-II with the IGF-1R (Byrd et al., J. Biol. Chem. 274:24408-16 (1999)).
IGF-1R blockade has been described as a tumor treatment; see, e.g., WO06138729, which describes methods of treating bone cancer, particularly metastatic bone cancer, by administering an IGF-1R antagonist and/or a PDGFR antagonist.
Acute respiratory distress syndrome (ARDS), first described in 1967 by Ashbaugh and colleagues (Ashbaugh D. G., et al., Lancet 2:319-323 (1967)) remains an important cause of morbidity and mortality in critically ill patients. ARDS is characterized by an acute pulmonary inflammatory process with epithelial apoptosis and interstitial and intra-alveolar edema, followed by fibroblast proliferation, migration, and fibrosis. The diagnosis of ARDS is based on clinical and radiographical criteria, including acute onset, bilateral infiltrates on chest radiograph, absence of congestive heart failure, and hypoxemia (Bernard G. R., et al., J Crit. Care 9:72-81 (1994)). This consensus definition has improved the standardization of clinical research and trials; however, it does not take into account the cause or mechanism of disease.
Much work has focused on the identification of humoral or cellular biological markers of ARDS in hopes that such markers may provide insight into the mechanisms of ARDS and improve the prediction of ARDS in high risk patients and prediction of outcome in ARDS patients (Pittet J. F., et al., Am J Respir Crit. Care Med 155:1187-1205 (1997)). To date, no single protein marker identified by traditional laboratory methods has demonstrated the specificity or sensitivity to serve as a reliable predictor of outcome.